ADAM9 promotes type I interferon-mediated innate immunity during encephalomyocarditis virus infection

Lindsey E. Bazzone, Junji Zhu, Michael King, GuanQun Liu, Zhiru Guo, Christopher R. MacKay, Pyae P. Kyawe, Natasha Qaisar, Joselyn Rojas-Quintero, Caroline A. Owen, Abraham L. Brass, William McDougall, Christina E. Baer, Timothy Cashman, Chinmay M. Trivedi, Michaela U. Gack, Robert W. Finberg and Evelyn A. Kurt-Jones ()
Additional contact information
Lindsey E. Bazzone: University of Massachusetts Chan Medical School
Junji Zhu: Cleveland Clinic
Michael King: University of Massachusetts Chan Medical School
GuanQun Liu: Cleveland Clinic
Zhiru Guo: University of Massachusetts Chan Medical School
Christopher R. MacKay: University of Massachusetts Chan Medical School
Pyae P. Kyawe: University of Massachusetts Chan Medical School
Natasha Qaisar: University of Massachusetts Chan Medical School
Joselyn Rojas-Quintero: Brigham and Women’s Hospital and Harvard Medical School
Caroline A. Owen: Brigham and Women’s Hospital and Harvard Medical School
Abraham L. Brass: University of Massachusetts Chan Medical School
William McDougall: University of Massachusetts Chan Medical School
Christina E. Baer: University of Massachusetts Chan Medical School
Timothy Cashman: University of Massachusetts Chan Medical School
Chinmay M. Trivedi: University of Massachusetts Chan Medical School
Michaela U. Gack: Cleveland Clinic
Robert W. Finberg: University of Massachusetts Chan Medical School
Evelyn A. Kurt-Jones: University of Massachusetts Chan Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)—a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis.

Date: 2024
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DOI: 10.1038/s41467-024-48524-6

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